Methods of Treating an Overweight or Obese Subject

ABSTRACT

The disclosure herein generally relates to methods of treating an over eight or obese condition, and overweight- or obesity-related conditions. In one embodiment, the disclosure provides a method of treating an overweight or obese condition involving administering to the subject in need thereof, an amount of a pharmaceutical composition including a MctAP-2 inhibitory compound, or a salt, ester, or prodrug thereof, effective to result in weight loss in the subject.

REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional applications U.S.Ser. No. 61/119,875 filed Dec. 4, 2008, U.S. Ser. No. 61/119,881 filedDec. 4, 2008, U.S. Ser. No. 61/119,884 filed Dec. 4, 2008, U.S. Ser. No.61/119,886 filed Dec. 4, 2008, U.S. Ser. No. 61/275,688 tiled Aug. 3,2009, and U.S. Ser. No. 61/260,194 filed Nov. 11, 2009, each applicationof which is hereby incorporated by reference.

BACKGROUND

Obesity is a complex medical disorder of appetite regulation andmetabolism resulting in excessive accumulation of adipose tissue mass.Typically defined as a body mass index (BMI) of 30 kg/m² or more,obesity is a world-wide public health concern that is associated withcardiovascular disease, diabetes, certain cancers, respiratorycomplications, osteoarthritis, gallbladder disease, decreased lifeexpectancy, and work disability. The primary goals of obesity therapyare to reduce excess body weight, improve or prevent obesity-relatedmorbidity and mortality, and maintain long-term weight loss.

Treatment modalities typically include lifestyle management,pharmacotherapy, and surgery. Treatment decisions are made based onseverity of obesity, seriousness of associated medical conditions,patient risk status, and patient expectations. Notable improvements incardiovascular risk and the incidence of diabetes have been observedwith weight loss of 5-10% of body weight, supporting clinical guidelinesfor the treatment of obesity that recommend a target threshold of 10%reduction in body weight from baseline values.

However, while prescription anti-obesity medications are typicallyconsidered for selected subjects at increased medical risk because oftheir weight and for whom lifestyle modifications (diet restriction,physical activity, and behavior therapy) alone have failed to producedurable weight loss, approved drugs have had unsatisfactory efficacy forseverely obese subjects, leading to only ˜3-5% reduction in body weightafter a year of treatment.

Bariatric surgery may be considered as a weight loss intervention forsubjects at or exceeding a BMI of 40 kg/m². Subjects with a BMI≧35 kg/m²and an associated serious medical condition are also candidates for thistreatment option. Unfortunately, postoperative complications commonlyresult from bariatric surgical procedures, including bleeding, embolismor thrombosis, wound complications, deep infections, pulmonarycomplications, and gastrointestinal obstruction; reoperation during thepostoperative period is sometimes necessary to address thesecomplications. Rates of reoperation or conversion surgery beyond thepostoperative period depend on the type of bariatric procedure, and inone study ranged from 17% to 31%. Intestinal absorptive abnormalities,such as micronutrient deficiency and protein-calorie malnutrition, alsoare typically seen with bypass procedures, requiring lifelong nutrientsupplementation. Major and serious adverse outcomes associated withbariatric surgery are common, observed in approximately 4 percent ofprocedures performed (including death in 0.3 to 2 percent of allpatients receiving laparoscopic banding or bypass surgeries,respectively).

MetAP2 encodes a protein that functions at least in part byenzymatically removing the amino terminal methionine residue fromcertain newly translated proteins such as glyceraldehyde-3-phosphatedehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increasedexpression of the MetAP2 gene has been historically associated withvarious forms of cancer. Molecules inhibiting the enzymatic activity ofMetAP2 have been identified and have been explored for their utility inthe treatment of various tumor types (Wang et al. (2003) Cancer Res.63:7861) and infectious diseases such as microsporidiosis,leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci. 9:34).However, such MetAP2 inhibitors may be useful as well for subjects withexcess adiposity and conditions related to adiposity including type 2diabetes, hepatic steatosis, and cardiovascular disease (via e.g.ameliorating insulin resistance, reducing hepatic lipid content, andreducing cardiac workload). Methods of treating obese subjects that aremore effective than e.g. dieting alone are clearly needed.

SUMMARY

The disclosure generally relates, at least in part, to methods fortreating a subject having an overweight or obese condition or a relatedcondition with pharmaceutical compositions including a MetAP-2inhibitory compound, or a salt or ester thereof. In one aspect, thedisclosure relates to methods of treating a subject having an overweightor obese condition including administering to the subject atherapeutically effective amount of a pharmaceutical composition asdisclosed herein, for example, a compound of Formula I, II, III, IV, V,VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, A-B, or C-D, and/or othercompounds as disclosed herein. In one embodiment, the subject has a BodyMass Index measurement of at least about 25 kg/m², at least about 30kg/², or at least about 40 kg/m².

In certain embodiments, the pharmaceutical composition is administerednon-parenterally, for example, orally, buccally, sublingually,transdermally, via inhalation, or rectally. In other embodiments, thepharmaceutical composition is administered parenterally, for example,subcutaneously.

In one embodiment, administration results in decreased body fat and asubstantial maintenance of muscle mass in the subject. In anotherembodiment, upon administration, fat oxidation is enhanced as comparedto a subject on a restricted food intake diet alone. In anotherembodiment, substantially no loss of new blood vessels in fat depositsoccur as compared to a subject being treated for obesity using an energyrestricted diet alone.

In one aspect, a disclosed method relates to controlling or preventinghepatic steatosis in an obese subject being treated for obesity,comprising administering a therapeutically effective amount of apharmaceutical composition including a compound disclosed herein. Alsoprovided herein is a method relating to improving liver function in anobese subject, including administering a therapeutically effectiveamount of a pharmaceutical composition including a compound describedherein to the subject.

In another aspect, a disclosed method relates to improving exercisecapacity in a subject in need thereof comprising administering atherapeutically effective amount of a pharmaceutical compositionincluding a compound described herein to the subject.

A method relating to reducing weight of a subject in a subject in needthereof is also contemplated herein, including administering atherapeutically effective amount of a pharmaceutical compositionincluding a compound described herein to the subject. For example, themetabolic rate of the subject may not substantially reduced as comparedto the metabolic rate of a subject on an energy restricted diet alone.In another aspect, a disclosed method relates to restoring normalmetabolic action in an obese subject in need thereof, includingadministering a therapeutically effective amount of a pharmaceuticalcomposition including a compound disclosed herein to the subject.

Also provided herein is a method relating to decreasing body fat in anoverweight or obese subject in need thereof, comprising administering atherapeutically effective amount of a pharmaceutical compositioncomprising a compound disclosed herein to the subject resulting in bodyfat reduction and substantial maintenance of muscle mass during the bodyfat reduction. In one embodiment, the subject retains substantially moremuscle mass as compared to body fat reduction in a subject using anenergy restricted diet alone.

In another aspect, a disclosed method relates to activating brown fatfunction and/or increasing brown fat tissue mass in a subject in needthereof, including administering a therapeutically effective amount of apharmaceutical composition including a compound disclosed herein to thesubject.

In another aspect, a disclosed method relates to restoring and/ormaintaining thyroid hormone concentrations in an obese subject,including administering a therapeutically effective amount of apharmaceutical composition including a compound described herein to thesubject.

In an exemplary embodiment, disclosed methods such as a method relatingto treating a subject having an overweight or obese condition, includesadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising the compound

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing effect of 7 days of administration of selectdisclosed compounds on body weight in DIO mice. Data is expressed asaverage weight of mice in grams.

DETAILED DESCRIPTION Overview

The disclosure is directed in part to methods of reducing adipose tissuein an overweight subject using compounds that modulate MetAP-2. AMetAP-2 inhibitory compound is able to inhibit the activity ofmethionine aminopeptidase 2 (MetAP-2), e.g., the ability of MetAP-2 tocleave the N-terminal methionine residue of newly synthesized proteinsto produce the active form of the protein. Exemplary MetAP-2 inhibitorsare provided herein.

Obesity and being overweight refer to an excess of fat in proportion tolean body mass. Excess fat accumulation is associated with increase insize (hypertrophy) as well as number (hyperplasia) of adipose tissuecells. Obesity is variously measured in terms of absolute weight,weight:height ratio, distribution of subcutaneous fat, and societal andesthetic norms. A common measure of body fat is Body Mass Index (BMI).The BMI refers to the ratio of body weight (expressed in kilograms) tothe square of height (expressed in meters). Body mass index may beaccurately calculated using the formulas: SI units:

BMI=weight(kg)/height²(m²), or US units:BMI=(weight(lb)*703/(height²(in²).

In accordance with the U.S. Centers for Disease Control and Prevention(CDC), an overweight adult has a BMI of 25 kg/m² to 29.9 kg/m², and anobese adult has a BMI of 30 kg/m² or greater. A BMI of 40 kg/m² orgreater is indicative of morbid obesity or extreme obesity. Forchildren, the definitions of overweight and obese take into account ageand gender effects on body fat.

BMI does not account for the fact that excess adipose can occurselectively in different parts of the body, and development of adiposetissue can be more dangerous to health in some parts of the body ratherthan in other parts of the body. For example, “central obesity”,typically associated with an “apple-shaped” body, results from excessadiposity especially in the abdominal region, including belly fat andvisceral fat, and carries higher risk of co-morbidity than “peripheralobesity”, which is typically associated with a “pear-shaped” bodyresulting from excess adiposity especially on the hips. Measurement ofwaist/hip circumference ratio (WHR) can be used as an indicator ofcentral obesity. A minimum WHR indicative of central obesity has beenvariously set, and a centrally obese adult typically has a WHR of about0.85 or greater if female and about 0.9 or greater if male.

Methods of determining whether a subject is overweight or obese thataccount for the ratio of excess adipose tissue to lean body mass involveobtaining a body composition of the subject. Body composition can beobtained by measuring the thickness of subcutaneous fat in multipleplaces on the body, such as the abdominal area, the subscapular region,arms, buttocks and thighs. These measurements are then used to estimatetotal body fat with a margin of error of approximately four percentagepoints. Another method is bioelectrical impedance analysis (BIA), whichuses the resistance of electrical flow through the body to estimate bodyfat. Another method is using a large tank of water to measure bodybuoyancy. Increased body fat will result in greater buoyancy, whilegreater muscle mass will result in a tendency to sink. Another method isfan-beam dual energy X-ray absorptiometry (DEXA). DEXA allows bodycomposition, particularly total body fat and/or regional fat mass, to bedetermined non-invasively.

Without being limited by any particular theory or mechanism of action,it is believed that fat oxidation and lipolysis are stimulated throughtreatment with inhibitors of MetAP2 that enhance the level and functionof thioredoxin and/or over-rides the inhibitory effects ofhyperinsulinemia related at least in part to insulin-stimulation and/orover-rides the inhibitory effects of high fat diet induced NADPH oxidaseactivity. A coordinated action can he induced which leads to aphysiological reduction in body adiposity through increased loss of fattissue-associated triglyceride, enhanced local generation of3,5,3′-triiodothyronine active thyroid hormone with correspondingenhanced activity of brown adipose tissue and its sensitivity tophysiological stimuli, increased metabolism of free fatty acids by theliver with increased ketone body formation, and reduced food intake.These effects are evident at doses of a MetAP2 inhibitor that do notsubstantially modulate angiogenesis.

In obese and/or hyperinsulinemic subjects, liver PKA function may besuppressed secondary to elevated NADPH oxidase expression. Ketone bodyproduction and utilization are typically suppressed in an obese subject,potentially reducing hepatic satiety signals and increasing foodconsumption. However, administration of a MetAP2 inhibitor, withoutbeing limited by an theory, leads to inhibition of thioredoxinamino-terminal methionine processing and increases steady-statethioredoxin levels, reactivating protein kinase A (PKA) function,reactivating adipose tissue lipase activity and/or stimulatingproduction and/or activity of the rate-limiting enzyme ofbeta-hydroxybutyrate production (3-hydroxymethyl glutaryl CoA synthase),leading to elevated ketone body production.

The coordinated and physiologic induction of anti-obesity activitiesmediated by the methods disclosed herein may lead to a healthy reductionin tissue levels of triglyceride, diacylglycerol, and other fat-relatedmediators and oxidants, and can result in a new steady state situationthat favors lean body composition and increased whole body energymetabolism. Without being bound by any theory, it is believed that themechanistic cascade activated by MetAP2 inhibitors leads to fat tissuebeing converted to ketone bodies and burned as fuel, unlike existingtherapies (including e.g., calorie or energy restricted diets) thattarget central control of food intake and that may carry adverse sideeffects (e.g. adverse neurological side effects). Further,therapeutically effective doses contemplated herein will not typicallyinduce any anti-angiogenic action.

An effective therapy for treating a subject having an overweight orobese condition may reduce adipose tissue without resulting indeleterious side effects, for example, wasting. Wasting is characterizedby degradation and loss of a substantial amount of lean body mass(muscle tissue, bones, and organs) in addition to adipose tissue. Inparticular, lean body mass refers to structural and functional elementsin cells, body water, muscle, bones, and other body organs such as theheart, liver, and kidneys. Although weight loss may involve loss of fatalong with slight loss of muscle or fluid, weight loss for the purposesof maintaining health should aim to lose fat while conserving lean bodymass. Wasting involves uncontrollable weight loss.

Treatment-induced wasting may occur as a side-effect of some drugs.High-dose sulphonamides, anti-mycobacterial agents, and othermedications have been associated with anorexia and subsequent wasting.Substantial loss of lean body mass can lead to various diseases.Schaafsma (Current Topics in Nutraceutical Research (2006) ISSN1540-7535 4(2):113-121). Health problems associated with loss of leanbody mass include difficulty fighting off infection, osteoporosis,decreased muscle strength, trouble regulating body temperature, and evenincreased risk of death.

MetAP-2 Compounds

Compounds for use with the methods disclosed herein include compounds ofFormula I:

in which: A is a Met-AP2 inhibitory core; W is O or NR₂; R₁ and R₂ areeach, independently, hydrogen or alkyl; X is alkylene or substitutedalkylene; n is 0 or 1; R₃ and R₄ are each, independently, hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; or R₃ and R₄, together with thecarbon atom to which they are attached, form a carbocyclic orheterocyclic group; or R₃ and R₄ together form an alkylene group; Z is—C(O)— alkylene or alkylene-C(O)—; and P is a peptide comprising from 1to about 100 amino acid residues attached at its amino terminus to Z ora group OR₅ or N(R₆)R₇, in which R₅, R₆ and R₇ are each, independently,hydrogen, alkyl, substituted alkyl, azacycloalkyl or substitutedazacycloalkyl; or R₆ and R₇, together with the nitrogen atom to whichthey are attached, form a substituted or unsubstituted heterocyclic ringstructure; or Z is —O—, —NR₈—, alkylene-O— or alkylene-NR₈—, where R₃ ishydrogen or alkyl; and P is hydrogen, alkyl or a peptide consisting offrom 1 to about 100 amino acid residues attached at its carboxy terminusto Z; in which the N-terminus of the peptide is —NR₂R₃, wherein R₂, ishydrogen, alkyl or arylalkyl and R₃, is hydrogen, alkyl, arylalkyl oracyl.

Exemplary compounds of Formula I include:

Further definitions and examples of substituents for each moiety inFormula I are shown in Olson et al. (U.S. Pat. No. 7,084,108 and WO2002/042295). Further embodiments and examples of the compounds ofFormula I are shown in Olson et al. (U.S. Pat. No. 7,084,108 and WO2002/042295). Methods of making compounds of Formula I are shown inOlson et al. (U.S. Pat. No. 7,084,108 and WO 2002/042295).

In other embodiments, compounds for use with the methods disclosedherein include compounds of Formula II:

in which: A is a MetAP-2 inhibitory core; W is O or NR; each R is,independently, hydrogen or alkyl; Z is —C(O)— or -alkylene-C(O)—; P isNHR, OR or a peptide consisting of one to about one hundred amino acidresidues connected at the N-terminus to Z; Q is hydrogen, a linear,branched or cyclic alkyl or aryl, provided that when P is —OR, Q is nothydrogen; or Z is-alkylene-O— or -alkylene-N(R)—; P is hydrogen or apeptide consisting of from one to about one hundred amino acid residuesconnected to Z at the carboxyl terminus; Q is hydrogen or a linear,branched or cyclic alkyl or aryl, provided that when P is hydrogen, Q isnot hydrogen: and pharmaceutically acceptable salts thereof. In arelated embodiment, when P is a peptide, the N-terminus of the peptideis —NR₂R₃, wherein R₂ is alkyl or arylalkyl and R₃ is hydrogen, alkyl,arylalkyl, or acyl.

Further definitions and examples of substituents for each moiety inFormula II are shown in Olson et al. (U.S. Pat. No. 6,548,477; U.S. Pat.No. 7,037,890; U.S. Pat. No. 7,084,108; U.S. Pat. No. 7,268,111; and WO2002/042295). Further embodiments and examples of the compounds ofFormula II are shown in Olson et al. (U.S. Pat. No. 6,548,477; U.S. Pat.No. 7,037,890; U.S. Pat. No. 7,084,108; U.S. Pat. No. 7,268,111; and WO2002/042295). Methods of making compounds of Formula II are shown inOlson et al. (U.S. Pat. No. 6,548,477; U.S. Pat. No. 7,037,890; U.S.Pat. No. 7,084,108; U.S. Pat. No. 7,268,111; and WO 2002/042295).

In other embodiments, compounds for use with the methods disclosedherein include compounds of Formula III:

in which: W is O or NR; each R is, independently hydrogen or aC₁-C₄-alkyl; Q is hydrogen, a linear, branched or cyclic C₁-C₆-alkyl; oraryl; R₁ is hydroxy, C₁-C₄-alkoxy or halogen; Z is —C(O)— orC₁-C₄-alkylene-C(O)—; P is NHR, OR, or a peptide comprising 1 to 100amino acid residues attached to Z at the N-terminus; or Z is alkylene-Oor alkylene-NR; and P is hydrogen or peptide comprising 1 to 100 aminoacid residues attached to Z at the C-terminus; or a pharmaceuticallyacceptable salt thereof. In related embodiments, when P is a peptide,the N-terminus of the peptide is —NR₂R₃, wherein R₂ is alkyl orarylalkyl and R₃ is hydrogen, alkyl, arylalkyl, or acyl.

Further definitions and examples of substituents for each moiety inFormula III are shown in Olson et al. (U.S. Pat. No. 6,548,477; U.S.Pat. No. 7,037,890; U.S. Pat. No. 7,084,108; U.S. Pat. No. 7,268,111;and WO 2002/042295). Further embodiments and examples of the compoundsof Formula III are shown in Olson et al. (U.S. Pat. No. 6,548,477; U.S.Pat. No. 7,037,890; U.S. Pat. No. 7,084,108; U.S. Pat. No. 7,268,111;and WO 2002/042295). Methods of making compounds of Formula III areshown in Olson et al. (U.S. Pat. No. 6,548,477; U.S. Pat. No. 7,037,890;U.S. Pat. No. 7,084,108; U.S. Pat. No. 7,268,111; and WO 2002/042295).

In other embodiments, the compounds for use with the methods disclosedherein include compounds of Formula A-B in which: A is a moiety selectedfrom the group consisting of:

in which R₂ is hydrogen or C₁-C₆-alkyl and X is halogen,dialkylsulfinium, thioalkoxy or thioaryloxy; and B is an alkanoyl,aroyl, carbamoyl or substituted carbamoyl group; or a pharmaceuticallyacceptable salt thereof.

In related embodiments, B is a moiety of the formula:

in which: R₃ is hydrogen or alkyl; R₄ and R₅ are each, independently,hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl or substituted or unsubstituted heteroalkyl;or R and R₅ together form an alkylene group; Z is —C(O)—or-alkylene-C(O)—; and P is —OR₆ or —N(R₇)R₈, wherein R₆, R₇ and R₈ areeach, independently, hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted aryl or substituted or unsubstitutedazacycloalkyl or R₇ and R₈, together with the nitrogen atom to whichthey are attached, form a heterocyclic ring structure.

In related embodiments, B is a moiety of the formula:

in which R₅ is substituted or unsubstituted linear, branched or cyclicC₁-C₆-alkyl, aryl, arylalkyl or heteroaryl; or R₃ and R₅ together form aC₃-C₆-alkylene group.

Further definitions and examples of substituents for each moiety inFormula A-B are shown in Olson et al. (WO 2005/066197). Furtherembodiments and examples of the compounds of Formula A-B are shown inOlson et al. (WO 2005/066197). Methods of making compounds of FormulaA-B are shown in Olson et al. (WO 2005/066197).

In other embodiments, the compounds for use with the methods disclosedherein include compounds of Formula C-D in which: C is a moiety of theformula:

and D is a moiety of the formula:

in which: n is independently an integer from 0-1; X is a linear orbranched (C₁-C₆-alkyl; Y is —C(O)—; R is NH; Z is a C₁-C₆-alkyl; and Pis NH₂ or a moiety of the formula:

Exemplary compounds of Formula C-D include:

Further definitions and examples of substituents for each moiety inFormula C-D are shown in Olson et al. (U.S. Pat. No. 7,084,108 and WO2002/042295). Further embodiments and examples of the compounds ofFormula C-I) are shown in Olson et al. (U.S. Pat. No. 7,084,108 and WO2002/042295). Methods of making compounds of Formula C-D are shown inOlson et al. (U.S. Pat. No. 7,084,108 and WO 2002/042295).

Methods disclosed here include administering a pharmaceuticalcomposition including disclosed compounds that may result in thedesirable effect of a reduction in adipose tissue but without resultingin deleterious side effects, for example, wasting. In certainembodiments, the compounds are compounds of Formula IV:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein a) —X is —OH; and —Y is chosen from halogen and,

wherein R₁ and R₂ are individually chosen from —H and substituted orunsubstituted lower alkyl, with the proviso that R₁ and R₂ are not both—H; and Z⁻ is a counter ion; or —X and —Y taken together form an oxiranering; and b) -A- is chosen from

wherein R₃ is chosen from substituted or unsubstituted lower alkyl,substituted or unsubstituted alkanoyl, substituted or unsubstitutedaryl, substituted or unsubstituted arylalkyl and arylalkanoyl.

Further definitions and examples of substituents for each moiety inFormula IV are shown in Hong et al. (U.S. Pat. No. 6,040,337). Furtherembodiments and examples of the compounds of Formula IV are shown in Ilong et al. (U.S. Pat. No. 6,040,337). Methods of making compounds ofFormula IV are shown in Hong et al. (U.S. Pat. No. 6,040,337).

In other embodiments, the compounds for use with the methods disclosedherein include compounds of Formula V:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,

-   wherein: a) X is —OH and Y is halogen or X and Y taken together form    an oxirane ring; b) B is selected from O and H₂; and c) R₁, R₂, R₃,    R₄ and R₅ are independently chosen from —H, —OH, acetoxy,    substituted or unsubstituted amino, substituted or unsubstituted    alkyl, substituted or unsubstituted aminoalkoxy, C₁-C₆ alkoxy,    halogen, cyano, trifluoromethyl, nitro, alkylenedioxy, formyl,    acetamido and methylenoxycarboxy, with the proviso that R₁, R₂, R₃,    R₄ and R₅ are not each —H. In a related embodiment, R₁, R₂, R₃, R₄    and R₅ are independently chosen from —H, —OH, acetoxy, amino,    alkylamino, dialkylamino, dialkylaminoalkyl, alkylaminoalkoxy,    dialkylaminoalkoxy, C₁-C₆ alkoxy, halogen, cyano, trifluoromethyl,    nitro, and methylenedioxy.

Further definitions and examples of substituents for each moiety inFormula V are shown in Hong et al. (U.S. Pat. No. 6,063,812 and WO1999/059986). Further embodiments and examples of the compounds ofFormula V are shown in Hong et al. (U.S. Pat. No. 6,063,812 and WO1999/059986). Methods of making compounds of Formula V are shown in Honget al. (U.S. Pat. No. 6,063.812 and WO 1999/059986).

In other embodiments, the compounds for use with the methods disclosedherein include compounds of Formula VI:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein A, B and C represent independently or simultaneously hydrogen,C₁-C₆ alkoxy, halogen, C₁-C₆ alkyl, trifluoromethyl, cyano, nitro,4-hydroxymethylphenoxy, —X—(CH₂)_(n)—OH or —X—(CH₂CH₂O)_(m)—CH₂CH₂OH,wherein X represents nitrogen or oxygen; n is 3, 4, 5 or 6; and m is 0,1 or 2, with proviso that at least one of above A, B, C is onesubstituent selected from 4-hydroxymethylphenoxy, —X—(CH₂)_(n)—OH or—X—(CH₂CH₂O)_(m)—CH₂CH₂OH.

Further definitions and examples of substituents for each moiety inFormula VI are shown in Lee et al. (WO 2006/080591). Further embodimentsand examples of the compounds of Formula VI are shown in Lee et al. (WO2006/080591). Methods of making compounds of Formula VI are shown in Leeet al. (WO 2006/080591).

In certain embodiments, the contemplated compounds include those ofFormula VII:

wherein: R₁ is a 2-methyl-1-propenyl or isobutyl group which may besubstituted by hydroxyl or di-C₁₋₃alkylamino; and R₂ is: (1) carbamoylwhich may optionally be substituted by (i) C₁₋₆alkyl which may besubstituted by halogen, di-C₁₋₃alkylamino, nitro, C₁₋₆alkyloxycarbonylor trimethylammonio halide, (ii) C₁₋₆alkanoyl which may be substitutedby di-C₁₋₃alkylamino, nitro, C₁₋₆alkanoyloxy, di-C₁₋₆alkylthio,C₁₋₆alkanoylthio, (iii) acryloyl or methacrylolyl, (iv) phenyl,naphthyl, benzoyl or benzenesulfonyl which may be substituted byhalogen, trifluoromethyl, chloromethyl, naphthyl, benzoyl, C₁₋₆alkyl,C₁₋₆alkoxy, di-C₁₋₃alkylamino, nitro, C₁₋₆alkanoyloxy orC₁₋₆alkanoylthio on the ring, (v) C₁₋₆alkoxycarbonyl,C₁₋₆alkoxycarbonylmethyl, or carboxymethyl, (vi) phenoxycarbonyl whichmay be substituted by halogen or C₁₋₆alkyl, (vii) amino, (viii)carbamoyl which may be substituted by C₁₋₆alkanoyl, halo-C₁₋₆-alkanoyl,naphthyl or benzoyl, or (ix) chloroacetyl; (2) benzenesulfonyl which maybe substituted by C₁₋₆alkyl or halogen; (3) C₁₋₆alkylsulfonyl; or (4)sulfamoyl which may be substituted by C₁₋₆alkyl or phenyl; or apharmaceutically acceptable salt, ester, or prodrug thereof.

Other contemplated compounds include O-chloroacetylcarbamoylfumagillol,O-chloroacetylcarbamoyldihydrofumagillol, orO-chloroacetylcarbamoyl-6′b-hydroxyfumagillol.

Further definitions and examples of substituents for each moiety inFormula VII are shown in Kishimoto et al. (U.S. Pat. No. 5,166,172; U.S.Pat. No. 5,698,586; U.S. Pat. Nos. 5,164,410; and 5,180,738). Furtherembodiments and examples of the compounds of Formula VII are shown inKishimoto et al. (U.S. Pat. No. 5,166.172; U.S. Pat. No. 5,698,586; U.S.Pat. Nos. 5.164,410; and 5,180.738). Methods of making compounds ofFormula VII are shown in Kishimoto et al. (U.S. Pat. No. 5,166,172; U.S.Pat. No. 5,698,586; U.S. Pat. Nos. 5,164,410; and 5,180,738).

In other embodiments, the compounds are compounds of Formula VIII:

wherein: A is halogen, —N(O)mR₁R₂, —N⁺R₁R₂R₃X⁻, —S(O)nR₁ orS⁺(O)mR₁R₂Xβ; and in which R₁, R₂ and R₃ independently are: (1) aC₁₋₆alkyl, C₂₋₆alkynyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₇₋₁₃aralkyl or C₆₋₁₀aryl group, each of which is unsubstituted orsubstituted by (i) C₁₋₆alkyl, (ii) C₂₋₆alkenyl, (iii) C₃₋₆alkynyl, (iv)C₃₋₆cycloalkyl, (v) C₃₋₆cycloalkenyl, (vi) C₆₋₁₀aryl, (vii) amino,(viii) C₁₋₆alkylamino, (ix) di-C₁₋₆alkylamino, (x) azido, (xi) nitro,(xii) halogen, (xiii) hydroxyl, (xiv) C₁₋₄alkoxy, (xv) C₆₋₁₀aryloxy,(xvi) C₁₋₆alkylthio, (xvii) C₆₋₁₀arylthio, (xviii) cyano, (xix)carbamoyl, (xx) carboxyl, (xxi) C₁₋₄alkoxycarbonyl, (xxii)C₇₋₁₁aryloxycarbonyl, (xxiii) carboxy-C₁₋₄alkoxy, (xxiv) C₁₋₆alkanoyl,(xxv) C₇₋₁₁aroyl, (xxvi) C₆₋₁₀arylsulfonyl, (xxvii) C₁₋₆alkylsulfinyl,(xxviii) C₆₋₁₀arylsulfinyl, (xxix) C₁₋₆alkylsufonyl, (xxx) a 5- or6-membered heterocyclic group containing 1 to 4 hetero atoms ofnitrogen, oxygen and/or sulfur, (xxxi) a 5- or 6-memberedheterocyclic-carbonyl group containing 1 to 4 hetero atoms of nitrogen,oxygen and/or sulfur, or (xxxii) a 5- or 6-membered heterocyclic-thiogroup containing 1 to 4 hetero atoms of nitrogen, oxygen and/or sulfurwhich may be fused with a benzene ring, wherein groups (i) to (xxxii)are unsubstituted or further substituted by one to three groups of anyof groups (i) to (xxxii) as defined above; or (2) a 5- or 6-memberedheterocyclic group containing 1 to 4 hetero atoms of nitrogen, oxygenand/or sulfur, which is unsubstituted or substituted by thesubstituent(s) on the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₇₋₁₃aralkyl or C₆₋₁₀aryl group asdefined in (1) of R₁, R₂ and R₃, and which may be fused with benzene,pyridine or cyclohexane; X⁺ is a counter anion; m is an integer of 0 or1; n is an integer of 0 to 2; R₁, and R₂ together with an adjacentnitrogen atom may form a 4 to 7 membered nitrogen-containingheterocyclic group which is unsubstituted or substituted by thesubstituent(s) on the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₇₋₁₃aralkyl or C₆₋₁₀aryl groups asdefined in (1) of R₁, R₂ and R₃, and which may be fused with benzene,pyridine, pyrazine, pyridazine, cyclohexane or cyclohexene, or R₁, andR₂ together with an adjacent sulfur atom may form a 4 to 7-memberedsulfur-containing heterocyclic group which is unsubstituted orsubstituted by the substituent(s) on the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₇₋₁₃aralkyl or C₆₋₁₀arylgroups as defined in (1) of R₁, R₂ and R₃, and which may be fused withbenzene, pyridine, pyrazine, pyridazine, cyclohexane or cyclohexene; Zis —NR₄ wherein R₄ is hydrogen, or a C₁₋₆alkyl or C₆₋₁₀aryl group, eachof which is unsubstituted or substituted by the substituent(s) on theC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl,C₇₋₁₃aralkyl or C₆₋₁₀aryl groups as defined in (1) of R₁, R₂ and R₃; Dis 2-methyl-1-propenyl or isobutyl; E is (i) hydrogen, (ii) a group asdefined in (1) of R₁, R₂ and R₃, or (iii) a C₁₋₁₀alkanoyl, C₇₋₁₁aroyl,5- or 6-membered heterocyclic carbonyl containing 1 to 4 hetero atoms ofnitrogen, oxygen and/or sulfur, carbamoyl, thiocarbamoyl,C₆₋₁₀arylsulfonyl, C₁₋₆alkylsulfonyl, sulfamoyl, C₂₋₇alkoxycarbonyl orC₇₋₁₁aryloxycarbonyl group which is unsubstituted or substituted by thesubstituent(s) on the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₇₋₁₃aralkyl or C₆₋₁₀aryl groups asdefined in (1) of R₁, R₂ and R₃, provided that, when A is chlorine, E isa group of (ii), or a group of (iii) excepting dinitrobenzoyl; or apharmaceutically acceptable, salt, ester, or prodrug thereof.

Further definitions and examples of substituents for each moiety inFormula VIII are shown in Kishimoto et al. (U.S. Pat. No. 5,180,735).Further embodiments and examples of the compounds of Formula VIII areshown in Kishimoto et al. (U.S. Pat. No. 5,180,735). Methods of makingcompounds of Formula VIII are shown in Kishimoto et al. (U.S. Pat. No.5,180,735).

In other embodiments, the compounds are compounds of Formula IX:

wherein: R₁ is 2-methyl-1-propenyl group or isobutyl group; R₂ is: (1)hydrogen atom, (2) a C₁₋₂₀alkyl group which may be substituted withamino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, nitro, halogen, hydroxyl,C₁₋₆alkylthio, C₁₋₆alkoxycarbonyl, carboxy-C₁₋₆carbamoyl, carboxyl,C₁₋₆alkoxycarbonyl, carboxy-C₁₋₆alkoxy, phenyl which may be substitutedby C₁₋₆alkyl, C₁₋₆alkoxy, halogen, halogenated alkyl or nitro, or (3) aC₆₋₁₂aryl group which may be substituted with C₂₋₆alkyl, (ii) amino,halogen, hydroxyl, C₁₋₆alkoxy, cyano, carbamoyl or carboxyl; R₃ is: (1)hydrogen atom, (2) a C₁₋₂₀alkyl group which may be substituted withamino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, nitro, halogen, hydroxyl,C₁₋₆alkylthio, C₁₋₆alkoxy, cyano, carbamoyl, carboxyl,C₁₋₆alkoxycarbonyl, carboxy-C₁₋₆alkoxy, phenyl which may be substitutedby C₁₋₆alkyl, C₁₋₆alkoxy, halogen, halogenated alkyl or nitro, or a 5-to 6-membered aromatic heterocyclic group containing 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur, and said alkyl group may beepoxidated at an optional position, (3) a C₁₋₂₀alkanoyl group which maybe substituted with amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, nitro,halogen, hydroxyl, C₁₋₆alkylthio, C₁₋₆alkoxy, cyano, carbamoyl,carboxyl, C₁₋₆alkoxycarbonyl, carboxy-C₁₋₆alkoxy, phenyl which may besubstituted by C₁₋₆alkyl, C₁₋₆alkoxy, halogen, halogenated alkyl ornitro, or a 5- to 6-membered aromatic heterocyclic group containing 1 to4 hetero atoms selected from nitrogen, oxygen and sulfur, (4) aC₆₋₁₀aroyl group which may be substituted with C₂₋₆alkyl, amino,halogen, hydroxyl, (v) C₁₋₆alkoxy, cyano, carbamoyl or carboxyl, (5)carbamoyl group which may be substituted with C₁₋₆alkyl, C₁₋₆alkanoyl,halogeno-C₁₋₆alkanoyl, C₁₋₆alkoxycarbonylmethyl, carboxymethyl, phenylwhich may be substituted by C₁₋₆alkyl, C₁₋₆alkoxy, halogen, halogenatedalkyl or nitro, naphthyl, benzoyl, naphthoyl or substituents formingcyclic amino group, taken together with the nitrogen atom of thecarbamoyl group, (6) benzenesulfonyl group which may be substituted withC₁₋₆alkyl or halogen, (7) a C₁₋₆alkylsulfonyl group which may besubstituted with the same substituents(s) as those of substitutedC₂₋₂₀alkanoyl group mentioned in above (3), (8) thiocarbamoyl groupwhich may be substituted with the same substituents(s) as those of asubstituted carbamoyl group mentioned in above (5), (9) aC₁₋₆alkoxycarbonyl group which may be substituted with the samesubstituent(s) as those of a substituted C₂₋₂₀alkanoyl group mentionedin above (3), (10) phenoxycarbonyl group which may be substituted withthe same substituent(s) as those of a substituted benzenesulfonyl groupmentioned in above (6), or (11) a 5- or 6-membered aromatic heterocycliccarbonyl group containing 1 to 4 hetero atoms selected from nitrogen,oxygen and sulfur which may be substituted with the same substituent(s)as those of a substituted C₆₋₁₀aroyl group mentioned in above (4),wherein said aromatic heterocyclic carbonyl group is selected from thegroup consisting of 2-furoyl, 2-thenoyl, nicotinoyl and isonicotinoyl;R₂ and R₃ may form pyrolidine, piperidine or isoindoline ring which maybe substituted with C₁₋₃alkyl or oxo; and the bonding mark

represents an α-linkage or β-linkage; or a pharmaceutically acceptablesalt, ester, or prodrug thereof.

Further definitions and examples of substituents for each moiety inFormula IX are shown in Kishimoto et al. (U.S. Pat. No. 5,288,722).Further embodiments and examples of the compounds of Formula IX areshown in Kishimoto et al. (U.S. Pat. No. 5,288,722). Methods of makingcompounds of Formula IX are shown in Kishimoto et al. (U.S. Pat. No.5,288,722).

In other embodiments, the compounds are compounds of Formula X:

wherein: R₁ is 2-methyl-1-propenyl group or isobutyl group; R₂ is: (1)hydrogen atom; (2) a C₁₋₂₀alkanoyl which may be substituted with anamino, hydroxyl, halogen or carboxyl; (3) a benzoyl or naphthoyl whichmay be substituted with a C₂₋₆alkyl, amino, halogen, hydroxyl, C.sub.1-6alkoxy, cyano, carbamoyl or carboxyl; (4) a 2-furoyl, 2-thienoyl,nicotinoyl, isonicotinoyl, or imidazole-1-carbonyl group which may besubstituted with a C₂₋₆alkyl, amino. halogen, hydroxyl, C₁₋₆alkoxy,cyano, carbamoyl or carboxyl; (5) carbamoyl which may be substitutedwith a C₁₋₆alkyl, C₁₋₆alkanoyl, chloroacetyl, dichloroacetyl,trichloroacetyl, C₁₋₆alkoxycarbonylmethyl, carboxymethyl, phenyl,naphthyl or benzoyl, or form a cyclic amino group together with theadjacent nitrogen atom selected from the group consisting ofpyrrolidino, piperidino, morpholino, piperazino or 4-phenylpiperazino;(6) a C₁₋₆alkoxycarbonyl which may be substituted with an amino,hydroxyl, halogen or carboxyl; (7) a phenoxycarbonyl which may besubstituted with a C₁₋₆alkyl or halogen; (8) a benzenesulfonyl which maybe substituted with one to three substituents selected from a C₁₋₆alkyland halogen; (9) a C₁₋₆alkylsulfonyl which may be substituted with anamino, hydroxyl, halogen or carboxyl; or (10) a sulfamoyl which may besubstituted with a C₁₋₆alkyl or phenyl; or a pharmaceutically acceptablesalt, ester, or prodrug thereof.

Further definitions and examples of substituents for each moiety inFormula X are shown in Kishimoto et al. (U.S. Pat. No. 5,204,345).Further embodiments and examples of the compounds of Formula X are shownin Kishimoto et al. (U.S. Pat. No. 5,204,345). Methods of makingcompounds of Formula X are shown in Kishimoto et al. (U.S. Pat. No.5,204,345).

In other embodiments, the compounds are compounds of Formula XI:

wherein: R₁ is hydrogen; R₂ is halogen, N(O)_(m)R₅R₆, N⁺R₅R₆R₇X⁻,S(O)_(n)R₅or S⁺R₅R₆X⁻, in which R₅, R₆ and R₇ represent eachindependently a substituted or unsubstituted hydrocarbon group or asubstituted or unsubstituted heterocyclic group; X⁻ represents a counteranion; m represents 0 or 1; n represents an integer of 0 to 2; or R₅ andR₆ together with the adjacent nitrogen or sulfur atom may form anitrogen- or sulfur-containing heterocyclic group which is substitutedor unsubstituted and may form a condensed ring; or R₁ and R₂ togetherare a chemical bond; R₃ is a substituted or unsubstituted2-methyl-1-propenyl group or a substituted or unsubstituted isobutylgroup; A is O or NR₈, in which R₈ represents hydrogen, a substituted orunsubstituted lower alkyl group or a substituted or unsubstituted arylgroup; and R₄ is hydrogen, a substituted or unsubstituted hydrocarbongroup or a substituted or unsubstituted acyl group; or a salt thereof,and a fatty acid ester of glycerin or polyglycerin wherein the fattyacid constituting the fatty acid ester is a saturated fatty acid having6 to 22 carbon atoms.

Further definitions and examples of substituents for each moiety inFormula XI are shown in Kishimoto et al. (U.S. Pat. No. 5,422,363).Further embodiments and examples of the compounds of Formula XI areshown in Kishimoto et al. (U.S. Pat. No. 5,422,363). Methods of makingcompounds of Formula XI are shown in Kishimoto et al. (U.S. Pat. No.5,422,363).

Methods disclosed herein include administering a pharmaceuticalcomposition including MetAP-2 inhibitory compounds that result in thedesirable effect of a reduction in adipose tissue but without resultingin deleterious side effects, for example, wasting. In certainembodiments, the compounds are compounds of Formula XII:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein: R₁, R₂, R₃, R₄, R₅ and R₆ can be the same or different fromeach other, and are hydrogen alkyl, aryl, halogen, hydroxyl, alkoxy,carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino,dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group,acyclic or aromatic cyclic group which can be optionally substituted, aheterocyclic or aromatic heterocyclic group which can be optionallysubstituted, a substituted aryl or aroyl group having at least onesubstituent selected from the group consisting of alkyl, amino, halogen,hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid,carboxyl ester, carboxyl salt, hydroxyl and alkylthioether; R₇ ishydrogen or an hydroxy group; and R₈ is (1) a substituted alkyl, allylor alkyne group; or (2) a substituted alkoxyl or thioalkoxyl group, ormethylene or ethylene alkoxyl or thioalkoxyl group, wherein themethylene or ethylene can be optionally substituted; or (3) an aroylgroup which can be optionally substituted with at least one substituentselected from the group consisting of alkyl, amino, alkylamino,dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl,thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxylsalt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic oraromatic cyclic groups which can be optionally substituted, or aheterocyclic or aromatic heterocyclic group which can be optionallysubstituted; or (4) an aryl group which can be optionally substitutedwith at least one substituent selected from the group consisting ofalkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy,cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid,carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substitutedureido, vinyl, cyclic or aromatic cyclic groups which can be optionallysubstituted, or a heterocyclic or aromatic heterocyclic group which canbe optionally substituted; or (5) an amino, alkylamino, dialkylamino,halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl,carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclicor aromatic cyclic groups which can be optionally substituted, aheterocyclic or aromatic heterocyclic group which can be optionallysubstituted, carboxylic acid, carboxyl ester, carboxyl salt; or (6) analkyl group which can be optionally substituted with N⁺P₁P₂P₃X⁻ orS⁺P₁P₂X⁻, wherein P₁, P₂ and P₃ can be the same or different and areeach an optionally substituted hydrocarbon or heterocyclic group and X⁻is a counter anion; or (7) 2-methyl-1-propenyl or an isobutyl groupwhich can be optionally substituted with hydroxyl, carbamoyl,carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido,alkyl, lower alkoxy, a substituted alkanoyl group, a cyclic or aromaticcyclic group which can be optionally substituted, a heterocyclic oraromatic heterocyclic group which can be optionally substituted, asubstituted aryl or aroyl group having at least one substituent selectedfrom the group consisting of alkyl, amino, halogen, hydroxyl, loweralkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester,carboxyl salt, hydroxyl or alkylthioether; or (8) 2-methyl-1-propenyl oran isobutyl group which can be optionally substituted with N⁺P₁P₂P₃X⁻ orS⁺P₁P₂X⁻, wherein P₁, P₂ and P₃ can be the same or different and areeach an optionally substituted hydrocarbon or heterocyclic group and Xis a counter anion; or (9) a benzenesulfonyl, methylsulfonyl or alkylsufonyl group, with or without a methylene or ethylene substituent, orthe corresponding amide or ester, which can be optionally substituted;or (10) an alkoxycarbonyl or phenoxycarbonyl group with or without amethylene or ethylene substituent, which can be optionally substituted.

Further definitions and examples of substituents for each moiety inFormula XII arc shown in Liu et al. (U.S. Pat. No. 6,207,704; U.S. Pat.No. 6,566,541; and WO 1998/056372). Further embodiments and examples ofthe compounds of Formula XII are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372). Methods ofmaking compounds of Formula XII are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372).

In other embodiments, the compounds are compounds of Formula XIII:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein: Z is an oxygen and can have R or S configuration; R₁, R₂, R₃,R₄, R₅ and R₆ can be the same or different from each other and arehydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl,carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido,lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclicgroup which can be optionally substituted, a heterocyclic or aromaticheterocyclic group which can be optionally substituted, a substitutedaryl or aroyl group having at least one substituent selected from thegroup consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy,cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt,hydroxyl and alkylthioether; R₇ and R₈ can be the same or different fromeach other and are: (1) hydrogen or a substituted alkyl, ally! or alkynegroup; (2) a substituted alkoxyl or thioalkoxyl group, or methylene orethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylenecan he optionally substituted; or (3) an aroyl group which can heoptionally substituted with at least one substituent selected from thegroup consisting of alkyl, amino, alkylamino, dialkylamino, halogen,hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl,carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl ordialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclicgroups which can be optionally substituted, or a heterocyclic oraromatic heterocyclic group which can be optionally substituted; or (4)an aryl group which can be optionally substituted with at least onesubstituent selected from the group consisting of alkyl, amino,alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido,carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxylester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido,vinyl, cyclic or aromatic cyclic groups which can be optionallysubstituted, or a heterocyclic or aromatic heterocyclic group which canbe optionally substituted; or (5) an amino, alkylamino, dialkylamino,halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl,carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclicor aromatic cyclic groups which can be optionally substituted, aheterocyclic or aromatic heterocyclic group which can be optionallysubstituted, carboxylic acid, carboxyl ester, carboxyl salt; or (6) analkyl group which can be optionally substituted with N⁺P₁P₂P₃X⁻ orS⁺P₁P₂X⁻, wherein P₁, P₂ and P₃ can be the same or different and areeach an optionally substituted hydrocarbon or heterocyclic group and Xis a counter anion; or (7) 2-methyl-1-propenyl or an isobutyl groupwhich can be optionally substituted with hydroxyl, carbamoyl,carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido,alkyl, lower alkoxy, a substituted alkanoyl group, acyclic or aromaticcyclic group which can be optionally substituted, a heterocyclic oraromatic heterocyclic group which can be optionally substituted, asubstituted aryl or aroyl group having at least one substituent selectedfrom the group consisting of alkyl, amino, halogen, hydroxyl, loweralkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester,carboxyl salt, hydroxyl or alkylthioether; or (8) 2-methyl-1-propenyl oran isobutyl group which can be optionally substituted with N⁺P₁P₂P₃X⁻ orS⁺P₁P₂X⁻, wherein P₁, P₂ and P₃ can be the same or different and areeach an optionally substituted hydrocarbon or heterocyclic group and Xis a counter anion; or (9) a benzenesulfonyl, methylsulfonyl or alkylsufonyl group, with or without a methylene or ethylene substituent, orthe corresponding amide or ester, which can be optionally substituted;or (10) an alkoxycarbonyl or phenoxycarbonyl group with or without amethylene or ethylene substituent, which can be optionally substituted.

Further definitions and examples of substituents for each moiety inFormula XIII are shown in Liu et al. (U.S. Pat. No. 6,207,704; U.S. Pat.No. 6,566,541; and WO 1998/056372). Further embodiments and examples ofthe compounds of Formula XIII are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372). Methods ofmaking compounds of Formula XIII are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372).

In other embodiments, the compounds are compounds of Formula XIV:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein: A is a halogen, N⁺P₁P₂P₃X⁻ or S⁺P₁P₂X⁻, wherein P₁, P₂ and P₃can be the same or different and are each an optionally substitutedhydrocarbon or heterocyclic group and X is a counter anion; R₁, R₂, R₃,R₄, R₅ and R₆ can be the same or different from each other, and arehydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl,carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido,lower alkoxy, a substituted alkanoyl group, acyclic or aromatic cyclicgroup which can be optionally substituted, a heterocyclic or aromaticheterocyclic group which can be optionally substituted, a substitutedaryl or aroyl group having at least one substituent selected from thegroup consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy,cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt,hydroxyl and alkylthioether; R₇ is hydrogen or an hydroxy group; and R₈is (1) a substituted alkyl, allyl or alkyne group; or (2) a substitutedalkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl orthioalkoxyl group, wherein the methylene or ethylene can be optionallysubstituted; or (3) an aroyl group which can be optionally substitutedwith at least one substituent selected from the group consisting ofalkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy,cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid,carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substitutedureido, vinyl, cyclic or aromatic cyclic groups which can be optionallysubstituted, or a heterocyclic or aromatic heterocyclic group which canbe optionally substituted; or (4) an aryl group which can be optionallysubstituted with at least one substituent selected from the groupconsisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl,lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl,carboxylic acid, carboxyl ester, carboxyl salt, alkyl ordialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclicgroups which can be optionally substituted, or a heterocyclic oraromatic heterocyclic group which can be optionally substituted; or (5)an amino, alkylamino. dialkylamino, halogen, hydroxyl, cyano, amido,carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxyl, alkyl,dialkylcarbamoyl, ureido, vinyl, cyclic or aromatic cyclic groups whichcan be optionally substituted, a heterocyclic or aromatic heterocyclicgroup which can be optionally substituted, carboxylic acid, carboxylester or carboxyl salt; or (6) 2-methyl-1-propenyl or an isobutyl groupwhich can be optionally substituted with hydroxyl, carbamoyl,carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido,alkyl, lower alkoxy, a substituted alkanoyl group, acyclic or aromaticcyclic group which can be optionally substituted, a heterocyclic oraromatic heterocyclic group which can be optionally substituted, asubstituted aryl or aroyl group having at least one substituent selectedfrom the group consisting of alkyl, amino, halogen, hydroxyl, loweralkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester,carboxyl salt, hydroxyl or alkylthioether; or (7) a benzenesulfonyl,methylsulfonyl or alkyl sufonyl group, with or without a methylene orethylene substituent, or the corresponding amide or ester which can beoptionally substituted; or (8) an alkoxycarbonyl or phenoxycarbonylgroup with or without a methylene or ethylene substituent, which can beoptionally substituted.

Further definitions and examples of substituents for each moiety inFormula XIV are shown in Liu et al. (U.S. Pat. No. 6,207,704; U.S. Pat.No. 6,566,541; and WO 1998/056372). Further embodiments and examples ofthe compounds of Formula XIV are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372). Methods ofmaking compounds of Formula XIV are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372).

In other embodiments, the compounds are compounds of Formula XV:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein: A is a halogen, N⁺P₁P₂P₃X⁻ or S⁺P₁P₂X⁻, wherein P₁, P₂ and P₃can be the same or different and are each an optionally substitutedhydrocarbon or heterocyclic group and X⁻ is a counter anion; R₁, R₂, R₃,R₄, R₅ and R₆ can be the same or different from each other and arehydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl,carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido,lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclicgroup which can be optionally substituted, a heterocyclic or aromaticheterocyclic group which can be optionally substituted, a substitutedaryl or aroyl group having at least one substituent selected from thegroup consisting of alkyl, amino, halogen, hydroxyl lower alkoxy, cyano,amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt,hydroxyl and alkylthioether; R₇ is hydrogen or an hydroxy group; and R₈is (1) hydrogen or a substituted alkyl, allyl or alkyne group; or (2) asubstituted alkoxyl or thioalkoxyl group, or methylene or ethylenealkoxyl or thioalkoxyl group, wherein the methylene or ethylene can beoptionally substituted; or (3) an aroyl group which can be optionallysubstituted with at least one substituent selected from the groupconsisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl,lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl,carboxylic acid, carboxyl ester, carboxyl salt, alkyl ordialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclicgroups which can be optionally substituted, or a heterocyclic oraromatic heterocyclic group which can be optionally substituted; or (4)an aryl group which can he optionally substituted with at least onesubstituent selected from the group consisting of alkyl, amino,alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido,carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxylester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido,vinyl, cyclic or aromatic cyclic groups which can he optionallysubstituted, or a heterocyclic or aromatic heterocyclic group which canbe optionally substituted; or (5) an amino, alkylamino, dialkylamino,halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl,carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclicor aromatic cyclic groups which can be optionally substituted, aheterocyclic or aromatic heterocyclic group which can be optionallysubstituted, carboxylic acid, carboxyl ester, carboxyl salt; or (6)2-methyl-1-propenyl or an isobutyl group which can be optionallysubstituted with hydroxyl, carbamoyl, carbonyldioxyl, thiohydroxyl,amino, alkylamino, dialkylamino, ureido, alkyl, lower alkoxy, asubstituted alkanoyl group, a cyclic or aromatic cyclic group which canbe optionally substituted, a heterocyclic or aromatic heterocyclic groupwhich can be optionally substituted, a substituted aryl or aroyl grouphaving at least one substituent selected from the group consisting ofalkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl,carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl oralkylthioether; or (7) a benzenesulfonyl, methylsulfonyl or alkylsufonyl group, with or without a methylene or ethylene substituent, orthe corresponding amide or ester, which can be optionally substituted;or (8) an alkoxycarbonyl or phenoxycarbonyl group with or without amethylene or ethylene substituent, which can be optionally substituted.

Further definitions and examples of substituents for each moiety inFormula XV are shown in Liu et al. (U.S. Pat. No. 6,207,704; U.S. Pat.No. 6,566,541; and WO 1998/056372). Further embodiments and examples ofthe compounds of Formula XV are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372). Methods ofmaking compounds of Formula XV are shown in Liu et al. (U.S. Pat. No.6,207,704; U.S. Pat. No. 6,566,541; and WO 1998/056372).

Methods

A method of treating obesity in a subject in need thereof is providedherein, comprising parenterally or non-parenterally administering atherapeutically effective amount of a MetAP2 inhibitor, such as adisclosed compound to said subject. In some embodiments, a contemplatedtherapeutically effective amount of a disclosed compound as describedbelow, does not substantially modulate or suppress angiogenesis, but isstill effective as MetAP2 inhibitor. The term “angiogenesis” is known topersons skilled in the art, and refers to the process of new bloodvessel formation, and is essential for the exponential growth of solidtumors and tumor metastasis. For example, provided herein is a method oftreating obesity in a subject in need thereof, comprising administeringa therapeutically effective amount of a MetAP2 inhibitor, e.g., adisclosed compound to said subject, wherein substantially no loss of newblood vessels in fat deposits or other tissue compartments occur ascompared to a subject being treated for obesity using an energyrestricted diet alone.

For example, disclosed compounds may irreversibly inhibit enzymaticactivity of MetAP2, leading to N-terminal acetylation and stabilizationof these proteins at doses considerably lower than those required tosuppress angiogenesis or tumor growth in vivo. Without being limited toany theory, the long-lasting covalent inhibition of MetAP2 enzymaticactivity driven by such MetAP2 inhibitors may be responsible for thesegregation of angiogenic effects from metabolic responses mediated byincreased thioredoxin and/or glyceraldehyde-3-phosphate levels in vivo.Alternatively, anti-tumor effects driven by angiogenesis inhibition mayrequire a more thorough starvation of the tumor by heavily restrictingblood supply, which requires high doses. Metabolic effects, however, mayrequire a minor and incomplete perturbation of the system which occursat lower doses and without any obvious direct effect on blood vessels.

Treated subjects used the disclosed methods may have a lower systemicexposure to said MetAP2 inhibitor as compared to a subject parenterallyadministered the same of amount of the MetAP2 inhibitor. In an exemplaryembodiment, the disclosed methods may result in less accumulation in thereproductive tract (e.g. testis) of a subject, for example, as comparedto the same amount of MetAP2 inhibitor subcutaneously administered.

Disclosed methods of treating obesity e.g by non-parenterally orparenterally administering a MetAP2 inhibitor, may result in decreasedbody fat and a substantial maintenance of muscle mass in said subject.In certain embodiments, upon administration, fat oxidation is enhancedin a subject as compared to a subject on a restricted food intake dietalone. For example, provided herein is a method of decreasing body finin an overweight or obese subject in need thereof, comprisingadministering a therapeutically effective amount of a MetAP2 inhibitorto said subject resulting in body fat reduction, and wherein saidsubject substantially maintains muscle mass during the body fatreduction. Such a subject may retain substantially more muscle mass ascompared to body fat reduction in a subject using an energy restricteddiet alone.

In some embodiments, disclosed methods, upon administration of adisclosed compound e.g. daily or weekly, for about 3, 4, 5 or 6 monthsor more may result in at least a 5%, 10%, 20%, or 30%, or more weightloss based on the subject's original weight. In an embodiment, weightloss following treatment with therapeutically effective doses of MetAP2inhibitors may substantially cease once a subject attains a normal bodycomposition. Without being limited to an theory, this may be due toreliance of the mechanism on re-establishing tone of adrenergic signaltransduction in tissues such as fat, liver, and/or skeletal muscle.

In an embodiment, provided herein is a method of maintaining a specifiedweight in a formerly obese subject, comprising administering atherapeutically effective amount of a a disclosed compound to saidsubject.

Also provided herein is a method for controlling or preventing hepaticsteatosis in an obese subject being treated for obesity, comprisingadministering a therapeutically effective amount of a a disclosedcompound to said subject. In another embodiment, a method for improvingliver function in an obese subject is provided, comprising administeringa therapeutically effective amount of a a disclosed compound to saidsubject. For example, a method of restoring normal metabolic action inan obese subject in need thereof is provided, comprising administering atherapeutically effective amount of a a disclosed compound to saidsubject. In an embodiment, a method of reducing weight of a subject in asubject in need thereof is provided comprising administering atherapeutically effective amount of a a disclosed compound to saidsubject wherein the metabolic rate of the subject is not substantiallyreduced as compared to the metabolic rate of a diet only subject on anenergy restricted diet alone. In a different embodiment, a method ofrestoring and/or maintaining thyroid hormone concentrations in an obesesubject is provided, comprising administering a therapeuticallyeffective amount of a a disclosed compound to said subject.

In an embodiment, a method of improving exercise capacity in a subjectin need thereof is provided that comprises administering atherapeutically effective amount of a a disclosed compound to saidsubject.

Also provided herein is a method of activating brown fat function in asubject in need thereof, comprising administering a therapeuticallyeffective amount of a disclosed compound to said subject.

Contemplated herein is a method of reducing the amount or frequency ofadministering supplemental insulin in a subject suffering from type 2diabetes, comprising administering a therapeutically effective amount ofa a disclosed compound to said subject. Such treatment may be directedto an obese or non-obese subject.

In an embodiment, a method for improving surgical outcome in an obesesubject in need thereof by reducing weight of said subject is providedcomprising administering a therapeutically effective amount of a adisclosed compound to said subject before non-acute surgery, therebyreducing liver and/or abdominal fat in said subject and improvingsurgical outcome. Such surgeries may include bariatric surgery,cardiovascular surgery, abdominal surgery, or orthopedic surgery.

In addition to being overweight or obese, a subject can further have anoverweight- or obesity-related co-morbidities, i.e., diseases and otheradverse health conditions associated with, exacerbated by, orprecipitated by being overweight or obese. Because being overweight orobese is associated with other adverse health conditions orco-morbidities, for example diabetes, administering a disclosed compoundbrings a benefit in ameliorating, arresting development of or, in somecases, even eliminating, these overweight- or obesity-related conditionsor co-morbidities. In some embodiments, methods provided herein mayfurther include administering at least one other agent that is directedto treatment of these overweight- or obesity-related conditions.

Contemplated other agents include those administered to treat type 2diabetes such as sulfonylureas (e.g., chlorpropamide, glipizide,glyburide, glimepiride); meglitinides (e.g., repaglinide andnateglinide); biguanides (e.g., metformin); thiazolidinediones(rosiglitazone, troglitazone, and pioglitazone); glucagon-like 1 peptidemimetics (e.g. exenatide and liraglutide); sodium-glucose cotransporterinhibitors (e.g., dapagliflozin), renin inhibitors, andalpha-glucosidase inhibitors (e.g., acarbose and meglitol), and/or thoseadministered to treat cardiac disorders and conditions, suchhypertension, dyslipidemia, ischemic heart disease, cardiomyopathy,cardiac infarction, stroke, venous thromboembolic disease and pulmonaryhypertension, which have been linked to overweight or obesity, forexample, chlorthalidone; hydrochlorothiazide; indapamide, metolazone;loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, lasix,torsemide); potassium-sparing agents (e.g., amiloride hydrochloride,spironolactone, and triamterene); peripheral agents (e.g., reserpine);central alpha-agonists (e.g., clonidine hydrochloride, guanabenzacetate, guanfacine hydrochloride, and methyldopa); alpha-blockers(e.g., doxazosin mesylate, prazosin hydrochloride, and terazosinhydrochloride); beta-blockers (e.g., acebutolol, atenolol, betaxolol,nisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate,metoprolol succinate, Nadolol, penbutolol sulfate, pindolol, propranololhydrochloride, and timolol maleate); combined alpha- and beta-blockers(e.g., carvedilol and labetalol hydrochloride); direct vasodilators(e.g., hydralazine hydrochloride and minoxidil); calcium antagonists(e.g., diltiazem hydrochloride and verapamil hydrochloride);dihydropyridines (e.g., amlodipine besylate, felodipine, isradipine,nicardipine, nifedipine, and nisoldipine); ACE inhibitors (benazeprilhydrochloride, captopril, enalapril maleate, fosinopril sodium,lisinopril, moexipril, quinapril hydrochloride, ramipril, trandolapril);angiotensin II receptor blockers (e.g., losartan potassium, valsartan,and Irbesartan); and combinations thereof, as well as statins such asmevastatin, lovastatin, pravastatin, simvastatin, velostatin,dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin,crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, andglenvastatin, typically for treatment of dyslipidemia.

Other agents that may be co-administered (e.g. sequentially orsimultaneously) include agents administered to treat ischemic heartdisease including statins, nitrates (e.g., Isosorbide Dinitrate andIsosorbide Mononitrate), beta-blockers, and calcium channel antagonists,agents administered to treat cardiomyopathy including inotropic agents(e.g., Digoxin), diuretics (e.g., Furosemide), ACE inhibitors, calciumantagonists, anti-arrhythmic agents (e.g., Sotolol, Amiodarone andDisopyramide), and beta-blockers, agents administered to treat cardiacinfarction including ACE inhibitors, Angiotensin II receptor blockers,direct vasodilators, beta blockers, anti-arrhythmic agents andthrombolytic agents (e.g., Alteplase, Retaplase, Tenecteplase,Anistreplase, and Urokinase), agents administered to treat strokesincluding anti-platelet agents (e.g., Aspirin, Clopidogrel,Dipyridamole, and Ticlopidine), anticoagulant agents (e.g., Heparin),and thrombolytic agents, agents administered to treat venousthromboembolic disease including anti-platelet agents, anticoagulantagents, and thrombolytic agents, agents administered to treat pulmonaryhypertension include inotropic agents, anticoagulant agents, diuretics,potassium (e.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem),Bosentan, Epoprostenol, and Sildenafil, agents administered to treatasthma include bronchodilators, anti-inflammatory agents, leukotrieneblockers, and anti-Ige agents. Particular asthma agents includeZafirlukast, Flunisolide, Triamcinolone, Beclomethasone, Terbutaline,Fluticasone, Formoterol, Beclomethasone, Salmeterol, Theophylline, andXopenex, agents administered to treat sleep apnea include Modalinil andamphetamines, agents administered to treat nonalcoholic fatty liverdisease include antioxidants (e,g., Vitamins F and C), insulinsensitizers (Metformin, Pioglitazone, Rosiglitazone, and Betaine),hepatoprotectants, and lipid-lowering agents, agents administered totreat osteoarthritis of weight-bearing joints include Acetaminophen,non-steroidal anti-inflammatory agents (e.g., Ibuprofen, Etodolac,Oxaprozin, Naproxen, Diclofenac, and Nabumetone), COX-2 inhibitors(e.g., Celecoxib), steroids, supplements (e.g. glucosamine andchondroitin sulfate), and artificial joint fluid, agents administered totreat Prader-Willi Syndrome include human growth hormone (HGH),somatropin, and weight loss agents (e.g., Orlistat, Sibutramine,Methamphetamine, Ionamin, Phentermine, Bupropion, Diethylpropion,Phendimetrazine, Benzphetermine, and Topamax), agents administered totreat polycystic ovary syndrome include insulin-sensitizers,combinations of synthetic estrogen and progesterone, Spironolactone,Eflornithine, and Clomiphene, agents administered to treat erectiledysfunction include phosphodiesterase inhibitors (e.g., Tadalatil,Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g.,Alprostadil), alkaloids (e.g., Yohimbine), and testosterone, agentsadministered to treat infertility include Clomiphene, Clomiphenecitrate, Bromocriptine, Gonadotropin-releasing Hormone (GnRH), GnRHagonist, GnRH antagonist, Tamoxifen/nolvadex, gonadotropins, HumanChorionic Gonadotropin (HCG), Human Menopausal Gonadotropin (HmG),progesterone, recombinant follicle stimulating hormone (FSH),Urofollitropin, Heparin, Follitropin alfa, and Follitropin beta, agentsadministered to treat obstetric complications include Bupivacainehydrochloride, Dinoprostone PGE2, Meperidine HCl,Ferro-folic-500/iberet-folic-500, Meperidine, Methylergonovine maleate,Ropivacaine HCl, Nalbuphine HCl, Oxymorphone HCl, Oxytocin,Dinoprostone, Ritodrine, Scopolamine hydrobromide, Sufentanil citrate,and Oxytocic, agents administered to treat depression include serotoninreuptake inhibitors (e.g., Fluoxetine, Escitalopram, Citalopram,Paroxetine, Sertraline, and Venlafaxine); tricyclic antidepressants(e.g., Amitriptyline, Amoxapine, Clomipramine, Desipramine, Dosulepinhydrochloride, Doxepin, Imipramine, Iprindole, Lofepramine,Nortriptyline, Opipramol, Protriptyline, and Trimipramine); monoamineoxidase inhibitors (e.g., Isocarboxazid, Moclobemide, Phenelzine,Tranylcypromine, Selegiline, Rasagiline, Nialamide, Iproniazid,Iproclozide, Toloxatone, Linezolid, Dienolide kavapyronedesmethoxyyangonin, and Dextroamphetamine); psychostimulants (e.g.,Amphetamine, Methamphetamine, Methylphenidate, and Arecoline);antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes,Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone,Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); andmood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproexsodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,Oxcarbazepine, and Topiramate), agents administered to treat anxietyinclude serotonin reuptake inhibitors, mood stabilizers, benzodiazepines(e.g., Alprazolam, Clonazepam, Diazepam, and Lorazepam), tricyclicantidepressants, monoamine oxidase inhibitors, and beta-blockers, andother weight loss agents, including serotonin and noradrenergicre-uptake inhibitors; noradrenergic re-uptake inhibitors; selectiveserotonin re-uptake inhibitors; and intestinal lipase inhibitors.Particular weight loss agents include orlistat, sibutramine,methamphetamine, ionamin, phentermine, bupropion, diethylpropion,phendimetrazine, benzphetermine, and topamax.

In some embodiments, contemplated methods may further comprisingassessing one or more indices of on-going weight loss, e.g. the ketonebody production level in a subject; and optionally adjusting the amountadministered; thereby optimizing the therapeutic efficacy of said MetAP2inhibitor.

Administration and Formulation

Pharmaceutical compositions having compounds disclosed herein can beadministered in the form of a free acid. Alternatively, a salt can beprepared by reacting compounds disclosed herein with a suitable base.Pharmaceutically acceptable salts illustratively include those that canbe made using the following bases: ammonia, L-arginine, benethamine,benzathene, betaine, bismuth, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethylenediamine,N-methylglucamine, hydrabamine, 1H-imidazole, lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide,triethanolamine, zinc hydroxide, diclyclohexlamine, or any otherelectron pair donor (as described in Handbook of Pharmaceutical Salts,Stan & Wermuth, VHCA and Wiley, Uchsenfurt-Hohestadt Germany, 2002).Esters disclosed herein may be prepared by reacting compounds disclosedherein with the appropriate acid under standard esterificationconditions described in the literature (Houben-Weyl 4th Ed. 1952,Methods of Organic Synthesis). Suitable esters include ethyl methanoate,ethyl ethanoate, ethyl propanoate, propyl methanoate, propyl ethanoate,and methyl butanoate.

Compounds disclosed herein may be administered using any amount and anyroute of administration effective for treating a subject having anoverweight or obese condition without substantially reducing lean bodymass of the subject. Thus, the expression “amount effective for treatinga subject having an overweight or obese condition”, as used herein,refers to a pharmaceutical composition having a sufficient amount ofcompounds disclosed herein, or salts or esters thereof, to beneficiallyresult in weight loss without deleterious side effects, such assubstantial reduction of lean body mass of the subject.

Dosage and administration are adjusted to provide sufficient levels ofcompounds disclosed herein, or salts or esters thereof, to maintain thedesired effect. Additional factors that may be taken into accountinclude the severity of the disease state, e.g., overweight, obese, ormorbidly obese; age, and gender of the subject; diet, time and frequencyof administration; route of administration; drug combinations; reactionsensitivities; and tolerance/response to therapy. Long actingpharmaceutical compositions might be administered hourly, twice hourly,every three to four hours, daily, twice daily, every three to four days,every week, or once every two weeks depending on half-life and clearancerate of the particular composition.

Therapeutic efficacy and toxicity of compounds disclosed herein, orsalts or esters thereof can be determined by standard pharmaceuticalprocedures. For example, therapeutic efficacy and toxicity can bedetermined by minimal efficacious dose or NOAEL (no observable adverseeffect level). Alternatively, an ED50 (the dose is therapeuticallyeffective in 50% of the population) and LD50 (the dose is lethal to 50%of the population) can he determined in cell cultures or experimentalanimals. The dose ratio of toxic to therapeutic effects is thetherapeutic index, and it can be expressed as the ratio, LD50/ED50.Pharmaceutical compositions that exhibit large therapeutic indices arepreferred.

Compounds disclosed herein, or salts or esters thereof, may beformulated in dosage unit form for ease of administration and uniformityof dosage. In general, the total daily usage of the compositionsdisclosed herein will be decided by the attending physician within thescope of sound medical judgment. The therapeutically effective dose canbe estimated initially either in cell culture assays or in animalmodels, as provided herein, usually mice, but also potentially fromrats, rabbits, dogs, or pigs. The animal model provided herein is alsoused to achieve a desirable concentration and total dosing range androute of administration. Such information can then be used to determineuseful doses and routes for administration in humans.

Contemplated herein are formulations suitable for non-parenteraladministration of a disclosed compound. For example, in certainembodiments, a subject may have a lower systemic exposure (e.g. at leastabout 2, 3, 5, 10, 20, or at least about 30% less systemic exposure) tothe non-parenterally administered (e.g. oral administration) of adisclosed compound as compared to a subject parenterally administered(e.g. subcutaneously) the same dose of the MetAP2 inhibitor.

Contemplated non-parenteral administration includes oral, buccal,transdermal (e.g. by a dermal patch), topical, inhalation, or sublingualadministration, or e.g., ocular, pulmonary, nasal, rectal or vaginaladministration. Contemplated parenteral administration includessubcutaneous, intravenous, intramuscular or intraperitonealadministration.

In another embodiment, provided herein are effective dosages, e.g. adaily dosage of a a disclosed compound, that may not substantiallymodulate or suppress angiogenesis. For example, provided here aremethods that include administering doses of a disclosed compound thatare effective for weight loss, but are significantly smaller doses thanthat necessary to modulate and/or suppress angiogenesis (which maytypically require about 12.5 mg/kg to about 50 mg/kg or more). Forexample, contemplated dosage of a disclosed compound in the methodsdescribed herein may include administering about 25 mg/day, about 10mg/day, about 5 mg/day, about 3 mg/day, about 2 mg/day, about 1 mg/day,about 0.75 mg/day, about 0.5 mg/day, about 0.1 mg/day, about 0.05mg/day, or about 0.01 mg/day. For example, an effective amount of thedrug for weight loss in a subject may be about 0.0001 mg/kg to about 25mg/kg of body weight per day. For example, a contemplated dosage mayfrom about 0.001 to 10 mg/kg of body weight per day, about 0.001 mg/kgto 1 mg/kg of body weight per day, about 0.001 mg/kg to 0.1 mg/kg ofbody weight per day or about 0.005 to about 0.04 mg/kg or about 0.005 toabout 0.049 mg/kg of body weight a day.

Contemplated methods may include administration of a compositioncomprising a disclosed compound, for example, hourly, twice hourly,every three to four hours, daily, twice daily, 1, 2, 3 or 4 times aweek, every three to four days, every week, or once every two weeksdepending on half-life and clearance rate of the particular compositionor inhibitor.

Treatment can be continued for as long or as short a period as desired.The compositions may be administered on a regimen of, for example, oneto four or more times per day. A suitable treatment period can be, forexample, at least about one week, at least about two weeks, at leastabout one month, at least about six months, at least about 1 year, orindefinitely. A treatment period can terminate when a desired result,for example a weight loss target, is achieved. For example, when aboutloss of about 20% body weight, about 30% body weight or more has beenachieved. A treatment regimen can include a corrective phase, duringwhich a a disclosed compound dose sufficient to provide reduction ofexcess adiposity is administered, followed by a maintenance phase,during which a lower dose sufficient to prevent re-development of excessadiposity is administered.

For pulmonary (e.g., intrabronchial) administration, compounds disclosedherein, or a salt or ester thereof, can be formulated with conventionalexcipients to prepare an inhalable composition in the form of a finepowder or atomizable liquid.

For ocular administration, compounds disclosed herein, or a salt orester thereof, can be formulated with conventional excipients in theform of eye drops or an ocular implant. Among excipients useful in eyedrops are viscosifying or gelling agents to minimize loss by lacrimationthrough improved retention in the eye.

Liquid dosage forms for oral or other systemic administration include,but are not limited to, pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active agent(s), the liquid dosage forms may contain inertdiluents commonly used in the art such as, for example, water or othersolvents, solubilizing agents and emulsifiers such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the ocular, oral, or othersystemically-delivered compositions can also include adjuvants such aswetting agents, and emulsifying and suspending agents.

Dosage forms for topical or transdermal administration of an inventivepharmaceutical composition include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants, or patches. The activeagent is admixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives or buffers as may berequired. For example, cutaneous routes of administration are achievedwith aqueous drops, a mist, an emulsion, or a cream.

Transdermal patches have the added advantage of providing controlleddelivery of the active ingredients to the body. Such dosage forms can hemade by dissolving or dispensing the compound in the proper medium.Absorption enhancers can also be used to increase the flux of thecompound across the skin. The rate can be controlled by either providinga rate controlling membrane or by dispersing the compound in a polymermatrix or gel.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium.

Compositions for rectal or vaginal administration may be suppositorieswhich can be prepared by mixing the active agent(s) disclosed hereinwith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active agent(s).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. Alternatively, formulations suitable foruse with the methods disclosed herein are incorporated into chewabletablets, crushable tablets, tablets that dissolve rapidly in within themouth, or mouthwash. In such solid dosage forms, the active agent ismixed with at least one inert, pharmaceutically acceptable excipient orcarrier such as sodium citrate or dicalcium phosphate and/or a) fillersor extenders such as starches, sucrose, glucose, mannitol, and silicicacid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as milksugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings, release controlling coatings and other coatings well known inthe pharmaceutical formulating art. In such solid dosage forms theactive agent(s) may be admixed with at least one inert diluent such assucrose or starch. Such dosage forms may also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. They mayoptionally contain opacifying agents and can also be of a compositionthat they release the active agent(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes.

In addition to being overweight or obese, a subject can further have anoverweight- or obesity-related co-morbidities, i.e., diseases and otheradverse health conditions associated with, exacerbated by, orprecipitated by being overweight or obese. Thus, a method of treating asubject having an overweight- or obesity-related condition is providedherein, the method involving administering to the subject atherapeutically effective amount of compounds disclosed herein, or asalt or ester thereof, such that the amount administered does notsubstantially reduce lean body mass of the subject.

For example, Type II diabetes has been associated with obesity. Certaincomplications of Type II diabetes, e.g., disability and premature death,can be prevented, ameliorated, or eliminated by sustained weight loss(Astrup, A. Pub Health Nutr (2001) 4:499-5 15).

Cardiac disorders and conditions, for example hypertension,dyslipidemia, ischemic heart disease, cardiomyopathy, cardiacinfarction, stroke, venous thromboembolic disease and pulmonaryhypertension, have been linked to overweight or obesity. For example,hypertension has been linked to obesity because excess adipose tissuesecretes substances that are acted on by the kidneys, resulting inhypertension. Additionally, with obesity there are generally higheramounts of insulin produced (because of the excess adipose tissue) andthis excess insulin also elevates blood pressure. A major treatmentoption of hypertension is weight loss.

Respiratory disorders and conditions such as obesity-hypoventilationsyndrome, asthma, and obstructive sleep apnea, have been linked to beingoverweight or obese. Elamin (Chest (2004) 125:1972-1974) discusses alink between being overweight or obese and asthma. Kessler et al. (EurRespir J (1996) 9:787-794) discusses a link between being overweight orobese and obstructive sleep apnea. Hepatic disorders and conditions,such as nonalcoholic fatty liver disease, have been linked to beingoverweight or obese. Tolman et al. (Ther Clin Risk Manag (2007)6:1153-1163) discusses a link between being overweight or obese andnonalcoholic fatty liver disease.

Because being overweight or obese is associated with the aboveconditions, administering pharmaceutical compositions having compoundsdisclosed herein bring a benefit in ameliorating, arresting developmentof or, in some cases, even eliminating, these overweight- orobesity-related conditions.

Incorporation by Reference

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

Equivalents

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to he considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

EXAMPLES Example 1 Orally Administered Compounds having MetAP-2Inhibitory Cores Cause Weight Loss in Diet-Induced Obese Mice

A weight loss study was conducted in obese mice. The mice in this studywere not genetically obese, but prior to and during the study, obesitywas induced by a high-fat diet. Twelve week-old C57BL/6NTac mice,maintained on a 60% fat diet prior to and during the study, wereseparated into seven groups, eight animals per group. Average bodyweight of the mice was approximately 47 g at the start of the study.

Each of six groups was orally administered 1.0 mg/kg of a compound(fumagillin and compounds B. C, D, E, F and G), in 10% gelucire indeionised water. Compounds B-G are as follows:

Each of these six groups was administered a different compound. Onegroup was orally administered fumagillin at 1.0 mg/kg (ZGN-201) in 10%gelucire in deionised water, and one group was administered 10% gelucirein deionised water (vehicle). Mice received administrations once a dayfor 7 days.

Data show that mice administered fumagillin lost the most weight overthe course of the 8 days (FIG. 1). Mice in groups B, C, D, and E alsolost weight over the course of the 8 days, with mice in group C losingthe most weight of these four groups (FIG. 1). (Data analyzed by ANCOVAwith body weight on Day 1 as covariate followed by multiple tests Sagainst vehicle group: *p<0.05; **p<0.01, ***p<0.001.)

1. A method of treating a subject having an overweight or obesecondition, the method comprising: administering to the subject in needthereof, a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula III:

wherein: W is O or NR; each R is, independently hydrogen or aC₁-C₄-alkyl; Q is hydrogen, a linear, branched or cyclic C₁-C₆-alkyl; oraryl; R₁ is hydroxy, C₁-C₄-alkoxy or halogen; and Z is —C(O)— orC₁-C₄-alkylene-C(O)—; and P is NHR, OR, or a peptide consisting of 1 toabout 100 amino acid residues attached to Z at the N-terminus; or Z isalkylene-O or alkylene-NR; and P is hydrogen or peptide comprising 1 to100 amino acid residues attached to Z at the C-terminus; or apharmaceutically acceptable salt, ester, or prodrug thereof.
 2. A methodof treating a subject having an overweight or obese condition, themethod comprising: administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprises a compoundselected from the group consisting of:


3. The method of claim 1, wherein the subject has a Body Mass Indexmeasurement selected from the group consisting of: at least about 25kg/m², at least about 30 kg/m², and at least about 40 kg/m².
 4. Themethod of claim 1, wherein the pharmaceutical composition isadministered non-parenterally.
 5. The method of claim 1, wherein thepharmaceutical composition is administered orally, buccally,sublingually, transdermally, via inhalation, or rectally.
 6. The methodof claim 1, wherein the pharmaceutical composition is administeredparenterally.
 7. The method of claim 1, wherein the pharmaceuticalcomposition is administered subcutaneously.
 8. The method of claim 1,wherein administration results in decreased body fat and a substantialmaintenance of muscle mass in the subject.
 9. The method of claim 1,wherein upon administration, fat oxidation is enhanced as compared to asubject on a restricted food intake diet alone.
 10. The method of claim1, wherein substantially no loss of new blood vessels in fat depositsoccur as compared to a subject being treated for obesity using an energyrestricted diet alone. 11.-15. (canceled)
 16. A method of decreasingbody fat in an overweight or obese subject in need thereof, comprisingadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula III to said subjectresulting in body fat reduction, and wherein said subject substantiallymaintains muscle mass during the body fat reduction.
 17. The method ofclaim 16, wherein the subject retains substantially more muscle mass ascompared to body fat reduction in a subject using an energy restricteddiet alone. 18.-19. (canceled)
 20. A method of treating a subject havingan overweight or obese condition, the method comprising: administeringto the subject in need thereof, a therapeutically effective amount of apharmaceutical composition comprising the compound